The inflammation caused by mechanical scars or various infection of bacteria et al is a normal response of human body associated with an edema, a pain etc. Generally, the syndrome of arthritic inflammation occurs temporally, however, it causes to long-term and eventual deformity if it is progressed to be severe. The arthritic disease can be classified into several diseases according to the respective disease such as rheumatoid arthritis (RA), rheumatic inflammation related disease etc. Among them, in particular, arthritic inflammation is the most frequently occurred and chronic disease characterized in the inflammatory change at the synovial membrane of the inner layer of articular capsule, which may progress to effect on all the joints of human body and become worse to be a disabled person. A progressive arthritic disease such as rheumatic arthritis gives rise to joint obstacle such as a joint aberrance and acampsia, which often results in severe physical disorder caused by the absence of effective treatment and continuous aggravation of the disease.
It has been known that osteoarthritis (OA) correlates with complex and multi-factors, however, most important factor among them is the inflammation of synovial fluid. The injury of synovial fluid may promotes the dissociation of proteoglycan (PG) as a result of the interaction between synovial cells and cartilage cells. The activated synovial cells reproduce numerous factors which may induce the loss of articular cartilage, for example, interleukin-1, tumor necrosis factor (TNF-alpha) and prostaglandins. The direct injury of cartilage cells further accelerates the reproduction of matrix metalloprotease (MMP) activating enzymes such as collagenase, stromelysin and gelatinase and various inflammatory mediators. Wherever the function of joint cartilage reduces, it gives rise to occurring OA diseases. The decrease of PGs at OA joint tissue reduces the resilence of cartilage, which endows cartilage cell, subcartilaginous osteocyte and synovial cell with a mechanical stress.
Both of OA and rheumatic arthritis (RA) are representative diseases destructing joint cartilage and being characterized in topical erosion of cartilage surface. For example, it has been reported that the introduction of radio-labeled sulfuric acid salt into the femoral joint cartilage of OA patients is significantly decreased compared with that of control group, which indicates that the dissociating rate of cartilage in OA patient is increased (Mankin et al., J. Bone Joint Surg., 52A, pp 424-434, 1970).
Four types of proteinase, i.e., serine, cystein, aspartic acid and metalloprotease exist in mammalian cell. The metalloprotease, one of the proteinase, has been reported to be an important factor for the extra-cellular substrate hydrolyzing action of joint cartilage in OA and RA patients and further the increased activity of collagenase and stromelysin has been found in the cartilage of OA patient, of which activity is closely interrelated with the severity of OA or RA disease (Mankin et al., Arthritis Rheum., 21, pp 761-766, (1978); Woessner et al., Arthritis Rheum., 26, pp 63-68, (1983) and Ibid., 27, pp 305-312, (1984)). Agrekanase has been also found in OA and RA patient recently and it shows metalloprotease enzyme similar activity and provides with the specific fragmented product of proteoglycans (Lohmander L. S. et al., Arthrits Rheum., 36, pp 1214-1222, 1993),
TNF (Tumor Necrosis Factor), a cytokine bound to cells, is processed from 36 kD precursor type to 17 kD activated or thereof. It has been found that TNF is a first controlling factor of acute phase response similar to the phenomenon occurred during inflammation, fever, acute infection and shock in human and animal, therefore the excess reproduction of TNF could be a cause of death. At present, it has been reported that the prevention of TNF reproduction could treat various diseases together with autoimmune disease such as rheumatoid arthritis (RA), insulin-independent diabetes and Crohn's disease (Lohmander L. S. et al., Arthritis Rheum., 36, pp 1214-1222, 1993; Macdonald T. et al., Clin. Exp. Immunol., 81, p 301, 1990).
Accordingly, the reproduction inhibitors of TNF have potentially therapeutic importance in the treatment of inflammatory diseases. Recently, matrix metalloprotease as well as other metalloproteases known to be as TNF-C (Tumor Necrosis Factor-Convertase, can be transformed from inactivated form thereof into activated form thereof (Gearing et al., Nature, 370, p 555 1994), therefore the inhibiting either the transformation of MPs or the release of activated TNF-alpha from the cell thereby may be an important mechanism in the treatment of inflammatory diseases.
Since the overproduction of TNF is a distinguished phenomenon in lots of diseases having characteristic of the tissue lysis mediated by MMP, the inhibitor of both MMP and TNF has favorable advantage in the treatment of specific inflammatory diseases correlated with both mechanism.
PCT WO 92/213260 A1 discloses N-carboxyalkylpeptidyl compounds useful as an enzyme inhibitor of hydroxamates and carboxylates matrix MMP; PCT WO 90/05716 A1 and PCT WO 92/13831 A1 disclose an hydroxamate matrix collagenase inhibitor; PCT WO 94/2446 A1 discloses natural amino acid derivatives useful as an MMP inhibitor; PCT WO 95/9841 A1 discloses hydroxamate derivatives useful as a cytokine inhibitor; GB A 2,268, 934 and PCT WO 94/24140 A1 disclose a hydroxamate inhibitor of MMP inhibiting TNF reproduction, the disclosure of which cited documents are incorporated herein by reference.
To treat RA or OA disease, conventional drugs for example, steroids such as cortisone and other ACTH (adrenocorticotrophic hormone); NSAID (Non-steroidal anti-inflammatory drug) such as aspirin, piroxicam, indomethacin etc; gold agents such as aurothioglucose, gold sodium thiomalate an auranofin etc; anti-rheumatic drug such as chloroquinone, D-penicillamine etc; gout inhibitors such as colchicines; and immuno-suppressing agents such as cyclophosphamide, azathioprine, methotrexate, levamisole etc have been prescribed till now. However, the treatment with conventional drugs has not provided with satisfactory efficacy and has various adverse effects, which limits the usage of conventional drugs.
For example, anti-inflammatory drugs such as asprin or butazolin have been used to alleviate the syndrome of OA and RAs, however, the consistent administration of the drugs is difficult because of their adverse effects, for example, i.e., severe stomach irritation resulting in gastritis, stomach ulcer etc.
Accordingly, there have been studied and investigated to develop new satisfactory anti-rheumatic agents which can solve the problems of conventional drugs, in particular, which can improve anti-inflammatory efficacy and provide with safe long-term administration without adverse action till now.
Present inventors extensively investigated to find new compounds showing strong inhibiting activity for the reproduction of NO and TNF-alpha, finally found new 2-oxo-heterocyclic compounds showing potent inhibition effects on the reproduction of NO and TNF-alpha, and completed present invention.